This proposal continues and extends previous efforts concerned with the development of animal analogues modeling different motivational aspects of cocaine dependence and the application of these analogues for the evaluation of potential treatment drugs. Studies conducted during the previous funding period examined the effects of pharmacological agents on the motivational strength of cocaine-seeking behavior as measured by the maintenance of operant responding by cocaine-associated environmental cues, the enhancement of this behavior by cocaine "priming" injections, the resistance to extinction of previously cocaine-reinforced responding, and responding on a multiple schedule involving drug vs. food-reinforced components. The present proposal extends these efforts by shifting emphasis to the investigation of relapse to cocaine-seeking behavior after prolonged extinction and abstinence. The clinical literature suggests that factors most commonly associated with relapse include re-exposure to a previously abused substance (priming effects), environmental stimuli associated with the reinforcing actions of the drug, and stressful events. Using a rat analog of "relapse" developed during the previous funding period, the objectives of this proposal are to evaluate the effects of ligands interacting with dopamine, serotonin, opioid, and glutamate transmission on the reinstatement of extinguished cocaine-seeking behavior induced by these stimulus conditions, and examine the neurobiological basis of "relapse" on the basis of the known pharmacological properties of compounds that selectively attenuate reinstatement of cocaine-seeking behavior. The Specific Aims are: (1) to continue previous efforts to evaluate the effects of potential treatment drugs in a model of "acute" cocaine-seeking behavior maintained by cocaine-associated conditioned stimuli and enhanced by "priming" injections of the drug, (2) to evaluate test drugs with regard to their ability to modify the reinstatement of cocaine-seeking behavior elicited either by a cocaine- associated environmental stimulus context or by cocaine "priming", (3) to evaluate test drugs by their ability to lower the resistance to extinction of previously cocaine-reinforced responding, and (4) to develop and apply for drug testing a model of stress-induced reinstatement of cocaine-seeking behavior. It is expected that the results of these studies will assist in the development of more effective pharmacotherapeutic treatment strategies for cocaine abuse, and advance the understanding of the neurobiology of relapse phenomena.